Study of a Drug Candidate, Mul-1867, for Inhalation Therapy of Fungal Pneumonia Caused by Clinical Isolates of Aspergillus fumigatus in a Murine Lung Infection Model

ASM Microbe 2017 (June 01-04, 2017, New Orleans, LA)

Study of a Drug Candidate, Mul-1867, for Inhalation Therapy of Fungal Pneumonia Caused by Clinical Isolates of Aspergillus fumigatus in a Murine Lung Infection Model

Publication Type

Conference paper

Authors

George Tetz

Victor Tetz

Abstract

Background
Fungal infections predominantly caused by Aspergillus spp. are the most common cause of morbidity in lung transplant recipients and occur in up to 35% recipients after lung transplantation. Today, many patients, before or after lung transplantation, receive prophylactic inhaled amphotericin B (AMB) to decrease the rate of fungal infection. However, numerous studies have suggested that these widely used antimycotics are losing their efficacy, especially in the immunocompromised. The aim of the present study was to investigate the potency of Mul-1867 as a prophylactic for fungal pneumonia.

Methods

We used clinical isolates of A. fumigatus from lung transplant recipients with cystic fibrosis. Two antifungal agents were tested: novel, broad-spectrum antimicrobial Mul-1867 (С426H852N204 * 60 HCl) and liposomal AMB. The minimal fungicidal concentrations (MFCs) were determined by the broth macrodilution method.
For in vivo studies, immunocompromised 8-week-old C57BL/6 mice were intranasally infected with A. fumigatus (6×108 cfu/mouse). Treatment with Mul-1867 or AMB was started 2 hours before (to modulate the prophylactic regimen) or 18 hours after infection, and administered by inhalation in a rodent inhalation chamber. Both drugs were used at concentration of 32 × minimum inhibitory concentration (MIC). Fungal burden in the lungs and spleen was determined.

Results

Mul-1867 exhibited effective antifungal activity against A. fumigatus with an MFC of 0.25 mg/L. AMB was less effective than Mul-1867 with an MFC of 8 mg/L.
Induced pneumonia caused the death of all control animals without treatment within 6 days. In the group administered Mul-1867 2 hours before the fungal challenge, no animals died until the end of the observation period, whereas 20% animals died in the group in which treatment was started 18 hours post infection.
Animals treated with AMB exhibited 30% and 60% mortality when the drug was administered 2 hours prior to the infection and 18 hours post infection, respectively. Microbiological analysis of the fungal burden from the lungs and spleen indicated a greater protective effect of Mul-1867.

Conclusion

In the current study, we found that a novel drug candidate, Mul-1867, exhibits effective antifungal activity in vitro and in vivo. Mul-1867 was found to be highly effective in both prophylaxis and treatment of fungal pneumonia.